Following Intracerebral Hemorrhage (ICH), the blood?brain barrier (BBB) is disrupted with associated edema and leukocyte extravasation from blood into the tissue/hematoma. Neutrophils, monocytes and lymphocytes enter brain. Increased neutrophils or increased neutrophil to lymphocyte ratio in humans are associated with worse ICH outcomes. Thus this proposal will examine gene expression in neutrophils, monocytes and T lymphocytes following ICH as compared to ischemic stroke and controls. ICH mortality is very high, with ICH volumes and edema volumes and causes of ICH being important factors in survival. Thus, this proposal will examine gene expression in neutrophils, monocytes and T lymphocytes as function of ICH volume, edema volume and ischemic lesion volume around ICH, as well as causes of ICH. We expect different blood/ leukocyte/ platelet profiles for different ICH volumes and different ICH causes that affect hematoma resolution, recurrent bleeding, and severity of recurrent bleeding that would be molecular targets for improving survival. Based upon very robust preliminary data we propose the following aims.
Aim #1 a. Demonstrate that proinflammatory genes are expressed at early times (12h, 1d, 3d) in neutrophils, M1 monocytes and specific T cell subsets (??T cells) following ICH; and immune-related repair genes in M2 monocytes and specific T cell subsets (e.g. T helper cells) are expressed at later times following ICH (3d, 7d); and, show the genes and pathways differ from those for ischemic stroke.
Aim #1 b. Demonstrate specific T cell, and T-cell receptor gene expression decreases in blood following ICH and this may correlate with decreased numbers of blood T lymphocytes (??T early; T helper, Tregs later).
Aim #2. Determine the genes and pathways that correlate with volume of ICH, edema and ischemic lesions around ICH over time, after accounting for differences in treatment for different sized ICH.
Aim #3 a. Identify specific genes and pathways associated with deep ICH related to hypertension compared to cortical lobar ICH related to probable CAA as defined by the modified Boston Criteria23-25.
Aim #3 b. Demonstrate that, though there are some common genes and pathways associated with all causes of ICH, there are large numbers of genes and pathways that are specific for each cause. The molecular underpinnings underlying human ICH are largely unexplored. Thus, this proposal will begin to increase our understanding of human ICH by identifying molecules that correlate with factors associated with ICH outcomes (neutrophils, monocytes, T lymphocytes, as well as ICH volumes and edema volumes, and causes of ICH) that might be treatment targets to improve ICH outcomes.
This proposal uses RNAseq to measure alternatively spliced mRNA transcript expression in the blood of patients with intracerebral hemorrhage compared to control and ischemic stroke patients. Transcript expression will be correlated with factors associated with poor ICH outcomes including neutrophils, monocytes, lymphocytes, ICH volume, edema volume, and different causes of ICH.
